1. Field of the Invention
The present invention relates to polypeptides which are useful as hypoglycemic agents.
2. Discussion of the Background
Diabetes mellitus is mainly classified into insulin-dependent diabetes mellitus and insulin-independent diabetes mellitus. In the former diabetes mellitus, .beta. cells of Langerhans' islet are destroyed by an autoimmune mechanism, whereby secretion of insulin is markedly decreased. For maintenance of life, it is essential to inject insulin every day.
In insulin-independent diabetes mellitus, which is assumed to amount to 95% of all patients with diabetes mellitus in Japan, impairment in the function of pancreatic .beta. cells is noted. That is, pancreatic .beta. cells of the patient with insulin-independent diabetes mellitus are characterized in that reactivity with glucose is reduced and as a result it is impossible to secret insulin in an amount sufficient to maintain homeostasis of blood sugar. It is quite unknown why such functional impairment occurs on pancreatic .beta. cells in insulin-independent diabetes mellitus.
Insulin is the most important hormone for maintaining homeostasis of blood sugar level and is secreted from .beta. cells of the endocrine gland in the pancreas. Pancreatic endocrinic tissue includes four kinds of cells: .alpha., .beta., .delta. and PP; which are known to secrete glucagon, insulin, somatostatin, pancreatic polypeptide, respectively. These four kinds of cells gather in large quantities to constitute the pancreatic endocrinic secretion tissue called Langerhans' islets. Langerhans' islets are sporadically present in pancreatic exocrinic secretion tissue and governed by abundant nerves and blood vessels.
There is no doubt that the most important factor for stimulating secretion of insulin from pancreatic .beta. cells is glucose. However, it is also believed that regulation with digestive hormones such as GIP etc., or with the autonomic nervous system is also physiologically significant. Furthermore, one cannot ignore that other pancreatic Langerhans' islet hormones, i.e., somatostatin etc., are associated with stimulation of insulin secretion.
As stated above, there are many factors which affect secretion of insulin but the mechanism of these factors on pancreatic .beta. cells is unclear in many cases.
In the treatment of diabetes mellitus, oral hypoglycemic agents and insulin therapy are used. Sulfonylureas exhibiting a hypoglycemic activity mainly via accelerated secretion of insulin, and biguanides showing a hypoglycemic activity mainly via the sugar metabolic system have been widely used in oral therapy, but these drugs are not always satisfactory in view of side effects. Insulin therapy is applied to the patient with diabetes mellitus who requires strict control of blood sugar. Since duration of the hypoglycemic activity of insulin is short, multiple insulin injections and continuous subcutaneous insulin injection are clinically adopted in therapy. However, the insulin therapy is painful to the patient and is known to be associated with side effects such as hypoglycemia, allergy, and lipoatrophy at the injected site.
The polypeptide BUF-3 is purified by using the differentiation induction to mouse Freund virus-inducing leukemia cells F5--5. BUF-3 has activity in differentiating and maturing mouse leukemia cells into normal cells (Japanese Patent Application Laid-Open Nos. 234097/1987 and 24070/1987), is used to treat anemia (Japanese Patent Application Laid-Open Nos. 234097/1987 and 24070/1987) and shows activity in secreting folicle stimulating hormone (Nature, 321, 776-779 (1986)).
BUF-3 is also called EDF (Erythroid Differentiation Factor) or FRP (FSH Releasing Protein). The older name BUF-3 is used herein.
It is known that polypeptide BUF-4 has the activity of secreting folicle stimulating hormone (Vale, W., River, J., Vaughan, J., McClintock, R., Corrigan, A., Woo, W., Karr, D. and Spiess, J., Nature, 321, 776-777 (1986)). BUF-4 is also called activin but the name BUF-4 is used herein.
Polypeptide BUF-5 is disclosed in Japanese Patent Application Laid-Open No. 119679/1988.
As described above, BUF-3, BUF-4 and BUF-5 are known and have the activity of releasing folicle stimulating hormone and the like, however hypoglycemic agents containing these polypeptides and a method of treating diabetes mellitus using these polypeptides are unknown.
A need exists therefore for additional hypoglycemic agents with reduced side effects and increased duration of effect.